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      Secretion of Glucose-Dependent Insulinotropic Polypeptide in Patients With Type 2 Diabetes : Systematic review and meta-analysis of clinical studies

      review-article
      Author(s): , MD 1 , 2 , , MD 1 , , MD, DMSC 1 , 3 , , MD 4 ,   , MD, DMSC 1 , , MD, DMSC 1 , , MD, PHD 1 , 3
      Publication date (Electronic):
      Journal: Diabetes Care
      Publisher: American Diabetes Association

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          Abstract

          OBJECTIVE

          To investigate glucose-dependent insulinotropic polypeptide (GIP) secretion in patients with type 2 diabetes and nondiabetic control subjects during oral glucose or meal tests.

          RESEARCH DESIGN AND METHODS

          Eligible trials were identified by The Cochrane Library, MEDLINE, Embase, and Web of Science. Data were retrieved and random-effects models for the primary meta-analysis, random-effects meta-regression, and subgroup and regression analyses were applied.

          RESULTS

          Random-effects meta-analysis of GIP responses in 23 trials during 28 different stimulation tests showed that patients with type 2 diabetes ( n = 363) exhibited no significant differences ( P = not significant) in peak plasma GIP, total area under the curve (tAUC), time-corrected tAUC (tAUC × min −1), and time-corrected incremental area under the curve (iAUC × min −1) in comparison with nondiabetic control subjects ( n = 325) but had lower GIP responses as evaluated from iAUC (weighted mean difference, −648 pmol/L × min; 95% CI, −1,276 to −21). Fixed-effects models meta-analyses confirmed most of the results of the primary meta-analysis but showed iAUC × min −1 to be reduced and showed tAUC and tAUC × min −1 to be higher in diabetic patients. Random-effects meta-regression of the primary meta-analysis showed that age (peak GIP, tAUC, iAUC, and iAUC × min −1), BMI (tAUC, iAUC, and iAUC × min −1), and HbA 1c (iAUC and iAUC × min −1) predicted some of the GIP outcomes. Post hoc subgroup analysis showed a negative influence of age and of HbA 1c on GIP responses and showed a positive influence of BMI on GIP responses.

          CONCLUSIONS

          Our results suggest that patients with type 2 diabetes are characterized by preserved GIP secretion in response to oral glucose and meal tests. They also suggest that high BMI is associated with increased GIP responses but increasing age and HbA 1c are associated with reduced GIP secretion.

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          Most cited references51

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          Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.

          M. Nauck, M. M. Heimesaat, C Orskov … (1993)
          In type-2 diabetes, the overall incretin effect is reduced. The present investigation was designed to compare insulinotropic actions of exogenous incretin hormones (gastric inhibitory peptide [GIP] and glucagon-like peptide 1 [GLP-1] [7-36 amide]) in nine type-2 diabetic patients (fasting plasma glucose 7.8 mmol/liter; hemoglobin A1c 6.3 +/- 0.6%) and in nine age- and weight-matched normal subjects. Synthetic human GIP (0.8 and 2.4 pmol/kg.min over 1 h each), GLP-1 [7-36 amide] (0.4 and 1.2 pmol/kg.min over 1 h each), and placebo were administered under hyperglycemic clamp conditions (8.75 mmol/liter) in separate experiments. Plasma GIP and GLP-1 [7-36 amide] concentrations (radioimmunoassay) were comparable to those after oral glucose with the low, and clearly supraphysiological with the high infusion rates. Both GIP and GLP-1 [7-36 amide] dose-dependently augmented insulin secretion (insulin, C-peptide) in both groups (P < 0.05). With GIP, the maximum effect in type-2 diabetic patients was significantly lower (by 54%; P < 0.05) than in normal subjects. With GLP-1 [7-36 amide] type-2 diabetic patients reached 71% of the increments in C-peptide of normal subjects (difference not significant). Glucagon was lowered during hyperglycemic clamps in normal subjects, but not in type-2 diabetic patients, and further by GLP-1 [7-36 amide] in both groups (P < 0.05), but not by GIP. In conclusion, in mild type-2 diabetes, GLP-1 [7-36 amide], in contrast to GIP, retains much of its insulinotropic activity. It also lowers glucagon concentrations.
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            Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses.

            M. Nauck, E Homberger, E Siegel … (1986)
            Integrated insulin secretion rates calculated from peripheral venous C-peptide measurements by two-compartment kinetic analysis were measured in six young normal subjects after increasing oral glucose loads of 25, 50, and 100 g and respective isoglycemic glucose infusions. The differences in B-cell secretory responses between oral and iv glucose challenges were attributed to factors other than glycemia itself (incretin effect). Both insulin and C-peptide concentrations as well as calculated integrated insulin secretion rates increased with increasing oral glucose loads. Due to the similarity in the glucose profiles after all oral loads, almost identical amounts of iv glucose (approximately 20 g) were infused in all "isoglycemic" infusion experiments, with resulting similar hormone profiles and insulin secretion rates. The percent contribution of incretin factors to total immunoreactive insulin responses after 25, 50, and 100 g glucose (85.6%, 74.9%, and 93.0%; response to oral load, 100%) was significantly higher than their contribution to integrated C-peptide responses (27.6-62.9%) or calculated integrated insulin secretion rates (19.2-61.0%). These findings indicate that the degree of incretin stimulation of insulin secretion depends on the amount of glucose ingested. A discrepancy between the estimates of the incretin effect derived from peripheral venous insulin responses, on the one hand, and C-peptide responses or calculated insulin secretion rates, on the other hand, exists. Inasmuch as peripheral insulin values reflect both insulin secretion and hepatic insulin removal, this discrepancy suggests that elimination kinetics of insulin differ between oral and iv glucose administration. This difference can be related to a significantly reduced fractional hepatic insulin extraction after oral (46.9-54.6%) compared to iv (63.4-76.5%) glucose administration when calculated by a three-compartment kinetic model. This reduction in fractional hepatic insulin extraction could be caused by gastrointestinal factors (hormones or nerves) stimulated in the course of glucose ingestion.
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              Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients.

              T Vilsbøll, T Krarup, C F Deacon … (2001)
              Incretin hormones importantly enhance postprandial insulin secretion but are rapidly degraded to inactive metabolites by ubiquitous dipeptidyl peptidase IV. The concentrations of the intact biologically active hormones remain largely unknown. Using newly developed assays for intact glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), we measured plasma concentrations after a mixed breakfast meal (566 kcal) in 12 type 2 diabetic patients (age 57 years [range 49-67], BMI 31 kg/m2 [27-38], and HbA1c 9.2% [7.0-12.5]) and 12 matched healthy subjects. The patients had fasting hyperglycemia (10.7 mmol/l [8.0-14.8]) increasing to 14.6 mmol/l (11.5-21.5) 75 min after meal ingestion. Fasting levels of insulin and C-peptide were similar to those of the healthy subjects, but the postprandial responses were reduced and delayed. Fasting levels and meal responses were similar between patients and healthy subjects for total GIP (intact + metabolite) as well as intact GIP, except for a small decrease in the patients at 120 min; integrated areas for intact hormone (area under the curve [AUC]INT) averaged 52 +/- 4% (for patients) versus 56 +/- 3% (for control subjects) of total hormone AUC (AUC(TOT)). AUC(INT) for GLP-1 averaged 48 +/- 2% (for patients) versus 51 +/- 5% (for control subjects) of AUC(TOT). AUC(TOT) for GLP-1 as well as AUC(INT) tended to be reduced in the patients (P = 0.2 and 0.07, respectively); but the profile of the intact GLP-1 response was characterized by a small early rise (30-45 min) and a significantly reduced late phase (75-150 min) (P < 0.02). The measurement of intact incretin hormones revealed that total as well as intact GIP responses were minimally decreased in patients with type 2 diabetes, whereas the late intact GLP-1 response was strongly reduced, supporting the hypothesis that an impaired function of GLP-1 as a transmitter in the enteroinsular axis contributes to the inappropriate insulin secretion in type 2 diabetes.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes Care
                Journal ID (iso-abbrev): Diabetes Care
                Journal ID (hwp): diacare
                Journal ID (pmc): dcare
                Journal ID (publisher-id): Diabetes Care
                Title: Diabetes Care
                Publisher: American Diabetes Association
                ISSN (Print): 0149-5992
                ISSN (Electronic): 1935-5548
                Publication date (Print): October 2013
                Publication date (Electronic): 14 September 2013
                Volume: 36
                Issue: 10
                Pages: 3346-3352
                Affiliations
                [1] 1Diabetes Research Division, Department of Medicine, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
                [2] 2Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy
                [3] 3Novo Nordisk Foundation Center for Basic Metabolic Research, Department of Biomedical Sciences, the Panum Institute, University of Copenhagen, Copenhagen, Denmark
                [4] 4Obesity Nutrition Research Center, St. Luke's/Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York.
                Author notes
                Corresponding author: Filip K. Knop, filipknop@ 123456dadlnet.dk .
                Article
                Publisher ID: 0465
                DOI: 10.2337/dc13-0465
                PMC ID: 3781498
                PubMed ID: 24065842
                SO-VID: d7a16c9c-90bc-43ed-8dbf-d8f38aadca54
                Copyright © © 2013 by the American Diabetes Association.
                License:

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                Date received : 25 February 2013
                Date accepted : 23 May 2013
                Page count
                Pages: 7
                Categories
                Subject: Meta-Analysis

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

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